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RESEARCH ARTICLE
Smart pH-responsive Co-polymeric Hydrogels for Controlled Delivery of
Capecitabine: Fabrication, Optimization and In Vivo Toxicology
Screening
Umaira Rehman
1
, Rai Muhammad Sarfraz
1,*
, Asif Mahmood
2
, Zahid Hussain
3
, Hnin Ei Thu
4
, Nadi-
ah Zafar
2
, Muhammad Umar Ashraf
2
and Nighat Batool
1
1
Department of Pharmaceutics, University of Sargodha, Sargodha, Pakistan;
2
Department of Pharmaceutics, The Uni-
versity of Lahore, Lahore, Pakistan;
3
Department of Pharmaceutics and Pharmaceutical Technology, College of Phar-
macy, University of Sharjah, Sharjah, United Arab Emirates;
4
Research and Innovation Department, Lincoln Universi-
ty College, Petaling Jaya 47301, Selangor, Malaysia
A R T I C L E H I S T O R Y
Received: September 06, 2020
Revised: November 16, 2020
Accepted: December 16, 2020
DOI:
10.2174/1567201818666210212085912
Abstract: Background: Despite exhibiting promising anticancer potential, the clinical significance
of capecitabine (a potent prodrug of 5-fluorouracil used for the treatment of colorectal cancer) is
limited owing to its acidic and enzymatic hydrolysis, lower absorption following the oral adminis-
tration, poor bioavailability, short plasma half-life, and poor patient compliance.
Objectives: The present study was aimed to fabricate the capecitabine as a smart pH-responsive hy-
drogel network to efficiently facilitate its oral delivery while shielding its stability in the gastric me-
dia.
Methods: The smart pH-sensitive HP-β-CD/agarose-g-poly(MAA) hydrogel network was devel-
oped using an aqueous free radical polymerization technique. The developed hydrogels were char-
acterized for drug-loading efficiency, structural and compositional features, thermal stability,
swelling behaviour, morphology, physical form, and release kinetics. The pH-responsive behaviour
of developed hydrogels was established by conducting the swelling and release behaviour at differ-
ent pH values (1.2 and 7.4), demonstrating significantly higher swelling and release at pH 7.4 as
compared with pH 1.2. The capecitabine-loaded hydrogels were also screened for acute oral toxici-
ty in animals by analysing the body weight, water and food intake, dermal toxicity, ocular toxicity,
biochemical analysis, and histological examination.
Results: The characteristic evaluations revealed that capecitabine (anticancer agent) was successful-
ly loaded into the hydrogel network. The range of capecitabine loading was from 71.22% to
90.12%. An interesting feature of hydrogel was its pH-responsive behaviour which triggers release
at basic pH (94.25%). Optimum swelling (95%)was seen at pH 7.4. Based upon regression coeffi-
cient R
2
(0.96 – 0.99) the best-fit model was zero-order. The extensive toxicity evaluations evi-
denced a good safety profile with no signs of oral, dermal, or ocular toxicities, as well as no varia-
tions in blood parameters and histology of vital organs.
Conclusion: Our findings conclusively evinced that the developed hydrogel exhibited excellent
pharmaceutical and therapeutic potential and thus can be employed as a pH-responsive system for
the controlled delivery of anticancer agents.
Keywords: Capecitabine, hydroxypropyl-β-cyclodextrin, agarose, hydrogel, controlled, release, colorectal cancer.
1. INTRODUCTION
A hydrogel is a hydrophilic 3-D polymeric network hav-
ing the capability to absorb excess water or physiological
fluid [1]. Hydrogels in swollen form resemble living tissues
*Address correspondence to this author at the Department of Pharmaceu-
tics, University of Sargodha, Sargodha, Pakistan;
E-mail: sarfrazrai85@yahoo.com
due to their soft and rubbery consistency and low interfacial
tension with water or biological fluids. These are non-irri-
tant, non-toxic, and biocompatible polymeric systems [2].
Due to their intrinsic properties, they exhibit numerous ad-
vantages as a drug delivery system such as the sustained re-
lease of encapsulated drugs. Physical and chemical cross-
linking techniques are used for the fabrication of hydrogels.
Chemically crosslinked hydrogels are formed due to cova-
lent interactions and physical gels are formed due to non-co-

2 Current Drug Delivery, 2021, Vol. 18, No. 0 Rehman et al.
valent interactions [3]. The presence of hydrophilic function-
al groups such as –OH, –COOH, -CONH2, -CONH, and
SO3H in the developed polymeric structure is responsible for
the absorption of a large amount of water by hydrogels and
is also helpful for the encapsulation of hydrophilic drugs.
Hydrogels have numerous applications in medicines and clin-
ical practice like tissue engineering and regenerative
medicine, cellular immobilization, diagnostics, separation of
biomolecules or cells, and barrier materials to regulate bio-
logical adhesions. Presently, hydrogels have been developed
in different forms like discs, microparticles, nanoparticles,
coatings, matrixes, composites, slabs, and films depending
upon the required use [4].
Hydroxypropyl-β-Cyclodextrin (HP-β-CD) is a useful cy-
clodextrin (CD)derivative because of its high solubility in
aqueous solution i.e. greater than 1200mg/ml. It is non-irri-
tant to skin, eyes, and mucosal linings [5]. Similarly,
agarose is a neutral linear polysaccharide consisting of
β-1,3-linked D-galactose and α-1, 4-linked 3,6-anhydro-α-L-
galactose. It dissolves in hot water at 60-70°C and forms a
thermoreversible gel on cooling (35-40°C). Moreover, it pos-
sesses the excellent gel-forming ability, swelling properties
in aqueous media, and mechanical properties. Hydrogels de-
veloped from pure agarose are clear, rigid, brittle, thermorev-
ersible, and offer a diffusion-assisted release of therapeutic
agents [6, 7].
Capecitabine is a prodrug of 5-fluorouracil and a potent
anticancer agent used for the treatment of colorectal cancer
at a dose of 41.66mg/kg two times a day. The anticancer
mechanism of capecitabine is attributed to its conversion to
5-fluorouracil in the tumour microenvironment by the enzy-
matic action, slowing down the tumour growth by inhibiting
the synthesis of DNA. Despite its potency as anticancer
agent, the clinical feasibility of capecitabine is limited due
to its erratic absorption, low bioavailability, fluctuating plas-
ma concentration, and early clearance from the body. More-
over, its therapeutic regimen (41.66mg/kg two times a day)
shows numerous adverse effects which also reduce patient
compliance. Therefore, in order to alleviate the aforemen-
tioned issues with the use of capecitabine, a newer sustained
release delivery system is needed for controlled release of
drugs in the plasma, improved plasma half-life, and im-
proved patient compliance [8].
The present study aimed to synthesize the capecitabine-
loaded HP-β-CD/agarose-co-methacrylic acid (MAA) hydro-
gels for controlled delivery of capecitabine by using a tech-
nique of free radical polymerization in which methylene bis
acrylamide (MBA) and ammonium persulfate (APS) were
used as crosslinker and initiator, respectively. To the best of
our knowledge, this is the pioneer study, which reveals the
use of these polymers for the development of hydrogel to re-
lease capecitabine at a controlled rate. The developed capec-
itabine-loaded hydrogels were characterized for various
physicochemical characterization, swelling ratio, thermal sta-
bility, and release kinetics. To further validate the safety of
the developed hydrogel, it was evaluated for acute oral toxic-
ity using rabbits.
2. MATERIALS AND METHODS
2.1. Materials
Capecitabine was purchased from Wuhanvanz Pharma,
Jingkai Future city Hubli, China. HP- β-CD (99%), agarose,
methacrylic acid (99%), N, N-methylene bisacrylamide
(99%), ammonium persulfate (99%), and methanol (99.7%)
were purchased from Sigma-Aldrich Co., St Louis, MO,
USA. Potassium dihydrogen phosphate, orthophosphoric
acid, and sodium hydroxide were purchased from Dae-Jung,
Korea. Distilled water was freshly prepared in the research
lab of the Faculty of Pharmacy, The University of Lahore.
All the chemicals used were of analytical grade.
2.2. Synthesis of HP-β-CD/agarose-g-poly(MAA) Hydro-
gels
The free radical polymerization technique was used for
the synthesis of HP-β-CD agarose hydrogels by using differ-
ent amounts of polymers, monomers, and crosslinkers.
Twelve formulations were developed (HPAG1 to HPAG12)
as shown in Table (1). For that, an accurate quantity of
agarose was weighed using an electronic weighing balance
(Shimadzu, AUW220D Japan) and poured into a specific
volume of hot distilled water (60-70 °C) with continuous stir-
ring on a hot plate magnetic stirrer until the solution became
clear. On the other hand, the weighed quantity of HP-β-CD
was dissolved in distilled water at room temperature. Similar-
ly, the solution of APS was prepared in a small volume of
distilled water separately, half of it was added to agarose so-
lution, and the remaining half was added into HP-β-CD solu-
tion dropwise to create active sites on polymer backbone
with thorough stirring. Afterward, both the polymer mix-
tures were mixed together thoroughly by the addition of HP-
β-CD solution into the agarose solution dropwise with cont-
inuous stirring. Monomer (MAA) was added in the above
mixture followed by the addition of cross-linker (MBA)
with continuous mixing. The final volume of the mixture
was achieved by adding the deionized distilled water. The
formed mixture was then subjected to thorough stirring until
a homogenous mixture was formed and then was transferred
to glass tubes which were sonicated for 3 to 5 min to remove
any dissolved gas. After the sonication, the glass tubes were
covered with aluminium foil and placed in the water bath
(Memmert) at different temperatures and duration such as
45°C for 1h, 50°C for 2 hours, 55°C for 4 hours, 60°C for 6
hours, and 65°C for 12 hours. After 24 hours, the formed hy-
drogels were removed by breaking the test tubes from the
backside and were cut into discs which were washed with
ethanol and distilled water solution (50:50) and dried in a
lyophilizer (Christ Alpha 1- 4 LD, Japan) at -55°C [9]. The
proposed chemical structure of HP-β-CD/agarose-g-poly
(MAA) hydrogels is presented in (Fig. 1).
2.3. Characterization
2.3.1. Loading of Capecitabine
Capecitabine was then loaded into the weighed dried
discs of different hydrogels. Briefly, 1% w/v solution of

Smart pH-responsive Hydrogels for Controlled Delivery of Capecitabine Current Drug Delivery, 2021, Vol. 18, No. 0 3
capecitabine was prepared by adding 1g of the drug in a
beaker containing a specified volume of phosphate buffer so-
lution (pH 7.4) and stirred on a hotplate magnetic stirrer at
room temperature for approximately 30 minutes to obtain a
clear solution. The pre-weighed hydrogel discs were soaked
in the prepared capecitabine solution until swelled to equilib-
rium. After removal from the drug solution, the swollen
discs were blotted with filter paper and dried in a hot air
oven (Memmert) at 45°C followed by drying at room tem-
perature.
2.3.2. Quantification of Capecitabine
The percentage of drug-loaded into hydrogels was calcu-
lated using the following equation:
Where, WD = final weight of dried discs of hydrogels af-
ter immersion in the drug solution
Wd = initial weight of dried hydrogel discs before immer-
sion in the drug solution.
2.3.3. In-Vitro Swelling Studies
The pH-responsive behaviour of hydrogels was evaluat-
ed by performing the swelling experiments. For that, the
dried discs were precisely weighed using an electric weigh-
ing balance (Shimadzu, AUW220D) and then placed in phos-
phate buffer solution (pH 7.4) at 37°C. After specified time
intervals (0.5, 1, 1.5, 2, 3, 4, 5, 6, 12, 18, 24, 30, 36, 42, and
48 hours) swollen discs were removed from the solution,
blotted with absorbent paper, and weighed again. The experi-
ment was continued until all the discs achieved a constant
weight. The following equation was used to calculate the per-
centage swelling of hydrogels [10].
Where, Wo is the initial weight of the dried disc and Wt
is the weight of swollen disc at time t.
Table 1. Composition of HP-β-CD/agarose-g-poly(MAA) hydrogels.
Codes
HP-β-CD
(g/100g)
Agarose
(g/100g)
MAA
(g/100g)
MBA
(g/100g)
APS
(g/100g)
HPAG1 0.5 0.25 10 0.15 0.15
HPAG2 1 0.25 10 0.15 0.15
HPAG3 1.5 0.25 10 0.15 0.15
HPAG4 0.5 0.5 10 0.15 0.15
HPAG5 0.5 1 10 0.15 0.15
HPAG6 0.5 1.5 10 0.15 0.15
HPAG7 0.5 0.25 15 0.15 0.15
HPAG8 0.5 0.25 20 0.15 0.15
HPAG9 0.5 0.25 25 0.15 0.15
HPAG10 0.5 0.25 10 0.17 0.15
HPAG11 0.5 0.25 10 0.20 0.15
HPAG12 0.5 0.25 10 0.23 0.15
Fig. (1). Proposed chemical structure of HP-β-CD/agarose-g-poly(MAA) hydrogel. (A higher resolution / colour version of this figure is avai-
lable in the electronic copy of the article).

2.3.4. Sol-gel Fraction
A sol-gel fraction was determined to find out the reac-
tants utilized during the synthesis of HP-β-CD/agarose-g-
poly(MAA) hydrogels. For that, dried discs were weighed
on an electronic weighing balance and crushed into small
pieces. Extraction was conducted in Soxhlet apparatus con-
taining boiling distilled water for 4 hours so that the co-poly-
meric network could be freed from unreacted reactants. The
extracted hydrogel pieces were removed using the filter pa-
per and dried at room temperature for 24 hours followed by
drying in a hot air oven at 40-45°C and were finally re-
weighed [11]. A sol-gel fraction was calculated by using the
following equations:
Where, Wo = Initial weight of dried disc before extrac-
tion and Wt = Final weight of dried disc after extraction.
Moreover, the Sol fraction was calculated by the following
expression:
Solfraction = 100 - gelfraction
2.3.5. Fourier-Transforms Infrared (FTIR) Spectroscopy
Pure capecitabine, HP-β-CD, agarose, physical mixture,
drug-loaded and unloaded hydrogels were subjected to FTIR
analysis to check the complex formation and compatibility
between the ingredients. All the samples were grounded and
dried after mixing with KBr, then 65 kN pressure was used
for 1 minute to convert into a disc having 12mm thickness.
Scanning of these samples was done at 4000 to 500cm
-1
us-
ing Thermos Fischer scientific Nicolet6700TM FTIR spec-
trophotometer [12].
2.3.6. Scanning Electron Microscopy (SEM)
The surface morphology and shape of prepared hydro-
gels were examined using the SEM (Vega 3, Tuscan). The
optimum size discs of dried hydrogel were cut and attached
with double adhesive tape on an aluminium stub. A gold
coating having a thickness of 300 Å was done on aluminium
stubs. The current of 10kV was set for scanning of coating
[13].
2.3.7. Differential Scanning Calorimeter (DSC)
Drug, polymers, monomer, and developed hydrogels
were also subjected to DSC studies in order to determine the
phase transition temperatures and heat of fusion under rising
temperature. Properly ground samples were covered in an
aluminium pan. Operation of SDT (Q600 TA USA) was car-
ried out at a rate of 10°C/min under nitrogen stream using a
temperature range of 0-400°C. The analysis was done in tri-
plicate for each sample [14].
2.3.8. Thermogravimetric Analysis (TGA)
The thermal stability of the newly developed polymeric
network compared to its individual formulation ingredients
at elevated temperature was determined using TGA thermal
analysis under the same conditions as in DSC.
2.3.9. Powder X-Ray Diffraction (PXRD) Analysis
PRXD Xpert having pan analytical software was used to
confirm the nature i.e. amorphous or crystalline of pure
capecitabine, polymers, and loaded hydrogels. Scanning was
done at 2θ = 10
o
-70
o
[15].
2.3.10. Elemental Dispersive X-ray Spectroscopy
The elemental composition and atomic weight of compo-
nents were determined using a microanalysis technique
which is energy dispersive spectroscopy. This technique was
utilized by using INCA 200 m oxford, UK, for developed hy-
drogels. The pure drug, unloaded, and loaded hydrogels
were subjected to energy dispersive spectroscopy and their
spectra were recorded [16].
2.4. In-Vitro Drug Release
To confirm the pH-responsive release of capecitabine
from hydrogels, the in-vitro drug release studies were car-
ried out at pH 1.2 and 7.4 using the USP dissolution appara-
tus Type-II containing 900 ml of buffer solution in each bas-
ket at 37 ± 0.5 °C. Paddle speed was kept at 50rpm. Sam-
pling was done at specified intervals i.e. 0.5, 1, 1.5, 2, 3, 4,
6, 8, 10, 12, 14, 16, 18, 20, 22 and 24hrs and UV visible
spectrophotometer was used for quantitative analysis of
capecitabine at λmax=300 nm [17].
2.5. Kinetic Model of Drug Release Data
Drug concentration, swelling, and diffusion rate are the
prime factors that affect drug release from the hydrogel.
Hence, the mechanism of capecitabine release from devel-
oped hydrogels was determined by applying the kinetic mod-
els (Zero order, First order, Higuchi, and Korsmeyer-Pep-
pas) on release data through DD solver adds in the option of
Microsoft Excel. Values of n and R
2
provided the mech-
anism of drug release and best fit model, respectively.
Fickian diffusion was governed by the value of “n” equal to
0.45, anomalous or non-fickian diffusion was shown by val-
ues ranging within 0.45-0.89, and case-II transport or ze-
ro-order was proved by a value equal to 0.89 [17].
Zero-order kinetics
Ft = Fo-Kot
First-order kinetics
In (1 - F) = - K1t
Higuchi model
Ft = KHt
1/2
Where, Ft = Fraction of drug release in time t, Fo= Total
amount of Capecitabine in polymeric networks, Ko K1, and
KH are the rate constants for Zero order, First order, and
Higuchi models, respectively.
Korsmeyer-Peppas model is described as;

Mt/M∞ shows the portion of Capecitabine released at
time t, K3 is rate constant and n describes release exponent.
2.6. Acute Oral Toxicity Studies Using an Animal Model
The acute oral toxicity of HP-β-CD/agarose-co-poly
(MAA) hydrogel on biochemical, lipid and renal profiles, vi-
tal organs, and physical activity of rabbits was carried out us-
ing the twelve healthy albino rabbits according to the OECD
guidelines. All the study protocols were reviewed and ap-
proved by the Institutional Research Ethics Committee of
Faculty of Pharmacy, The University of Lahore notification
no. IREC-2019-137A.The experimental animals were accli-
matized in stainless steel cages for 7 days and were fed with
a proper diet and water. Rabbits were divided into two
groups i.e. group A (control) and group B (test) by keeping
six rabbits in each group. Following the overnight fasting, a
dose of 2 g/kg of finely crushed hydrogel was administered
to each animal of the group B via the feeding tube, and both
the groups were kept under observation for food consump-
tion and water intake, body weight, skin allergies, and any
physical changes for 14 days. On 7
th
day, the blood samples
were collected from each animal. Prior to blood collection,
the ears of animals were cleaned off hairs by applying hair
removal cream and 2-3ml of the blood sample was collected
from the marginal vein of the ear by using 3cc syringes (In-
jekt
®
) and then transferred into EDTA tubes. The collected
blood samples were subjected to centrifugation for 15 min-
utes (Hitachi Zentrifugen EBA 20, Hitachi Ltd., Tokyo, Ja-
pan) at 5000 rpm for haematological analysis, AST, ALT,
lipid, and renal profile. After 14 days, all rabbits were re-
weighed and then anesthetized by injecting them with a com-
bination of ketamine and xylazine (70:30) at a dose of
1ml/kg into their thigh muscles. Blood samples were with-
drawn again by heart puncture, and vital organs (heart, liver,
kidney, lungs, intestine, stomach, spleen, and brain) were re-
moved and washed with PBS. These organs were then
stored in 10% formalin solution for microscopic evaluation
using H&E histological examination [18].
3. RESULTS AND DISCUSSION
3.1. Drug Loading Efficiency into a Hydrogel
Capecitabine was loaded into the hydrogel by diffusion
method. The entrapment of capecitabine into different hydro-
gel formulations was expressed as percent drug loading. The
resulting data presented in Fig. (2) showed that the loading
efficiency of capecitabine was found to be optimum in
HPAG9 hydrogel formulation (approximately 90%), com-
pared to HPAG1-HPAG3 hydrogels (approximately 80% to
87.31%), HPAG4-HPAG6 (70% to 85%). Results have also
revealed that the drug-loading efficiency of capecitabine
was exponentially increased by increasing the concentration
of HP-β-CD, agarose, and MAA contents, while drug load-
ing efficiency was decreased with an increase in MBA con-
tents (Fig. 2).
Fig. (2). Effect of concentration of ingredients on capecitabine loading efficiency, (A) Hydroxypropyl beta cyclodextrin (HP-β-CD) (B)
Agarose (C) Methacrylic acid (MAA) and D) Methylene bis acrylamide (MBA). (A higher resolution / colour version of this figure is avail-
able in the electronic copy of the article).

3.2. Swelling Behaviour
The effect of different concentrations of HP-β-CD,
agarose, MAA, and MBA on the swelling behaviour of hy-
drogels has also been evaluated at pH 7.4 (Fig. 3). Results
showed that the swelling was found to increase with an in-
crease in HP-β-CD, agarose, and MAA concentration while
swelling decreased by increasing MBA contents. The in-
creasing HP-β-CD contents resulted in a parallel increase in
swelling tendency from 88% to 95% for formulations
HPAG1 to HPAG3, respectively (Fig. 3A). HP-β-CD is a
highly hydrophilic polymer that is enriched in hydroxyl
groups that undergo deprotonation at pH 7.4 along with ion-
ized carboxylate groups (pKa = ͠4.5–5)from MAA induce re-
pulsion, causing considerable expansion of polymeric
chains. The swelling percentage was also increased from
71.33% to 78.99% in HPAG4 to HPAG6 formulations with
an increase in agarose contents (Fig. 3B). This slight rise in
swelling was expected to be due to ionization of hydroxyl
groups attached to the monosaccharide units of agarose
thereby causing the repulsion between polymeric chains, re-
sulting in swelling and uptake of swelling media. However,
this swelling was lower compared with HP-β-CD due to its
less hydrophilic nature at low temperature. Our results were
in agreement with a previous study in which researchers de-
veloped agarose and polyvinyl alcohol-based hydrogels and
observed poor swelling behaviour in agarose-based hydrogel
formulations [19].
Similarly, our results have also revealed a significant in-
crease in swelling from 89.54% to 97% (p<0.05, ANOVA)
in hydrogel formulations (HPAG7 to HPAG9) by increasing
the MAA contents (Fig. 3C). This effect may be attributed
to the availability of more carboxylate ions at pH 7.4 result-
ing in polymeric repulsion and expansion of hydrogel net-
work, leading to greatly improved uptake of swelling media
due to the availability of more free volume within the hydro-
gel network. Our results were also in agreement with the pre-
vious study in which researchers developed dual-responsive
(pH and temperature) hydrogels by free radical polymeriza-
tion technique and found that MAA-concentration depen-
dent on the increase in swelling of developed hydrogel [20].
On the other hand, a significant decrease in the swelling
tendency of hydrogel from 85.45% to 72.45% was observed
by increasing the MBA contents (Fig. 3D). This was expect-
ed to be associated with an increased cross-linking density
which leads to a reduction in network interconnected pores
and ultimately halted the diffusion process. Our results were
in agreement with previous studies in which Tanan and col-
leagues developed natural polymer-based hydrogels involv-
ing MBA as cross-linker [21].
Fig. (3). Effect of concentration of different ingredients on the swelling tendency of a hydrogel, (A) Hydroxypropyl beta cyclodextrin (H-
P-β-CD), (B) Agarose (C) Methacrylic acid (MAA), and (D) Methylene bis acrylamide (MBA). (A higher resolution / colour version of this
figure is available in the electronic copy of the article).

Fig. (4). Gel fraction (%) of hydrogel formulations (HPAG1 –HPAG12). (A higher resolution / colour version of this figure is available in
the electronic copy of the article).
3.3. Analysis of Sol-gel Fraction
A sol-gel fraction was determined to observe the effect
of formulation ingredients on gel fraction. Gel fraction of all
formulations (HPAG1-HPAG12) was ranged from 80.88%
to 94.12%. By increasing the quantities of polymer,
monomer, and cross-linker, a consistent increase in gel frac-
tion was noticed. In HPAG1 to HPAG3hydrogel formula-
tions, gel fraction was increased from 83.28% to 92.85%,
while inHPAG4 to HPAG6 hydrogel formulations, gel frac-
tion was ranged from80.88% to 89.12% that was less as com-
pared to HP-β-CD-based formulations (Fig. 4). This compar-
ative decrease in gel fraction may be due to the availability
of less reactive hydroxyl groups from agarose at the reaction
temperature. A rise in MAA contents has promoted gel frac-
tion from 82.15 to 94.12% due to the existence of more reac-
tive free radicals (deprotonated carboxylate ions) at pH 7.4.
This character also facilitates the rapid propagation of poly-
merization. Formulations containing MBA (HPAG10 to
HPAG12) have exhibited a 82.43 to 91.15% rise in gel frac-
tion due to high crosslinking density and higher polymeriza-
tion. Fekete and co-researchers developed hydrogels contain-
ing MBA as cross-linker. Similar findings in terms of gel
fraction were noted [22].
3.4. FTIR Analysis
FTIR analysis was performed to validate the structural
and compositional features of developed hydrogel formula-
tions as well as successful loading of capecitabine (Fig. 4).
IR spectrum of capecitabine presented evident peaks at
1035.13cm
-1
(C-F stretching vibrations), 1240cm
-1
(tetrahy-
drofuran ring), 1650.15cm
-1
(pyrimidine carbonyl stretching
vibrations), 1697.20cm
-1
and 1720.11cm
-1
(urethane car-
bonyl stretching vibrations), 3100.21cm
-1
(N-H stretching)
and 3300cm
-1
(O-H stretching vibrations) (Fig. 5C). Typical
bands of agarose were present at 1030.16cm
-1
, 1450.09cm
-1
,
1680.23cm
-1,
and 3640.19cm
-1
due to C-O bending, C-C bend-
ing, C=O stretching, and OH stretching, respectively (Fig.
5A). Prominent peaks of HP-β-CD displayed at
1040.1cm
-1
(C=O vibrations), 1651.24cm
-1
(H-O-H bending),
2980.19cm
-1
(C-H stretching) and 3610cm
-1
(O-H stretching)
(Fig. 5B).
FTIR spectrum of MBA showed distinct peaks at
1650.10cm
-1
, 3000.13cm
-1
, 3100cm
-1
and 3300.20cm
-1
corre-
sponding to C=O stretching, symmetric –CH2 stretching,
asymmetric –CH2 stretching, and N-H stretching vibrations,
respectively. No remarkable variations were seen in the IR
spectrum of the physical mixture thereby ensured the ingredi-
ent’s compatibility (Fig. 5D). IR spectra of capec-
itabine-loaded and unloaded hydrogels have presented the
typical peaks of both individual polymers with sound varia-
tions. The peak observed at 3610cm-1
due to O-H groups in
HP-β-CD spectrum was displaced to 3730.11cm
-1
while the
peak at 1450.09cm
-1
(C-C bending) of agarose was shifted to
the 1500.15cm-1
within spectrum of a drug-loaded network.
Furthermore, capecitabine peaks at 1650.15cm
-1
and
1720.11cm
-1
due to carbonyl groups of pyrimidine and ure-
thane groups respectively were shifted to 1625.20cm-1
and
1661.15cm
-1
. Peaks at 3640.19 cm
-1
due to –OH group
stretching in agarose were shifted to 3730.11cm
-1
. Peaks at
2980.19 cm-1
due to C-H stretching in HP-β-CD were shifted
to 2970.0cm
-1
. Moreover, the intensity of peak due to tetrahy-
drofuran ring (1240 cm
-1
) was markedly reduced in capec-
itabine loaded network (Fig. 5F). The switching of peaks
and variation in their intensities confirmed new polymer syn-
thesis.
3.5. Scanning Electron Microscopy (SEM)
The surface morphology of developed pH-sensitive hy-
drogel was investigated using SEM analysis at different mag-
nifications. The resulting photomicrograph revealed that hy-
drogels were having cracks on their surfaces (Fig. 6). The
presence of cracks on the surface of the developed hydrogel
was expected due to excessive drying during lyophilisation
at -55°C. These cracks may facilitate the uptake of dissolu-
tion media into the hydrogel network. Upon complete
swelling, the volume of cracks was reduced due to repulsion
of polymeric chains and resulted in slow release of capec-
itabine. Other researcher works pertaining to hydrogel sur-
face morphology and the presence of cracks [23] have also
obtained similar findings.

3.6. Thermal Analysis
The thermal behaviour of pure capecitabine, HP-β-CD,
agarose, and capecitabine-loaded hydrogel was analyzed us-
ing DSC and TGA analyses. DSC analysis is performed to
evaluate the structural and functional features of materials as
a function of temperature. DSC analysis of pure capec-
itabine, HP-β-CD, agarose, and capecitabine-loaded hydro-
gel was performed (Fig. 7A). DSC curve of capecitabine has
shown an endothermic peak at 132.31°C (0.02265J/g) corre-
sponding to the melting range of capecitabine, validating its
crystalline nature. Another peak at 159.70°C (0.004427J/g)
was due to partial degradation of capecitabine while the
peak at 456.35°C (0.0007347J/g) was attributed to its com-
plete combustion. HP-β-CD presented an endothermic peak
at 68.5°C (0.02845J/g) due to loss of moisture contents
while peaks at 322.78°C (0.0007733J/g) and 455.36°C
(0.005812J/g) were due to melting and complete combustion
of HP-β-CD, respectively. Agarose displayed slight en-
dothermic peaks at 105.02°C (0.06403J/g) corresponding to
the loss of moisture contents and at 311.45°C (0.04048J/g)
due to phase transition and partial combustion. A sharp
exothermic peak was also observed at 439.46°C
(0.02918J/g) which was due to the complete combustion of
agarose. In the case of a drug-loaded hydrogel, a slight en-
dothermic peak observed near 106.67°C (0.06964J/g) was
due to moisture loss while peak seen at 348.67°C
(0.005809J/g) indicated the change of state from solid into a
liquid. Capecitabine incorporation and conversion into an
amorphous state were evident from the drug-loaded DSC
thermogram as no drug peak was observed. Moreover, the
peak presented above 500°C depicted the complete combus-
tion of a polymeric network (Fig. 7A).
Fig. (5). FTIR spectra of (A) Agarose (B) HP-β-CD (C) Capecitabine (D) Physical mixture (E) Unloaded hydrogel (F) Drug loaded hydro-
gels.

Fig. (6). SEM photomicrograph of capecitabine-loaded hydrogels.
Fig. (7A). DSC analysis of HP-β-CD, agarose, capecitabine, and capecitabine-loaded hydrogel. (A higher resolution / colour version of this

Fig. (7B). TGA analysis of HP-β-CD, agarose, capecitabine, and capecitabine-loaded hydrogel. (A higher resolution / colour version of this
TGA analysis of pure drug, polymers, and drug-fabricat-
ed hydrogel was performed to evaluate mass loss against in-
creasing temperature. TGA thermogram of capecitabine dis-
played gradual decline in mass with increasing temperature
i.e. 92.24% (134.22°C), 71.62% (179.09°C), 45.73%
(296.39°C) and 23.22% (494.74°C). In the case of HP-β-
CD, initially, 9.68% weight loss was recorded at 82.40°C
that was further increased to 13.24% at temperature
312.03°C (above the melting point of HP-β-CD), 76.59% at
378.86°C, and 91.046% at 517.49°C. Similarly, for agarose,
gradual decrease in intact mass was noted i.e. 85.15%,
81.73%, 40.22%, and 17.26% against temperature
101.60°C, 277.20°C, 336.91°C, and 460.61°C, respectively.
Moreover, capecitabine-loaded network depicted 86.35% in-
tact mass at 99.47°C, 77.16% at 225.30°C, 66.59% at
346.87°C, 45.74% at 373.88°C and 19.50% of remaining
mass at 552.32°C (Fig. 7B). Hence, the developed co-poly-
meric network was more stable as compared to ingredients.
3.7. XRD Analysis
Powder X-ray diffraction studies on pure ingredients and
fabricated networks were conducted to check their physical
nature (amorphous or crystalline). HP-β-CD diffractogram
presented fused peaks thereby reflecting amorphous nature.
Capecitabine showed intense and differentiated peaks at 2Ɵ
= 10.75
o
, 18.95
o
, 19.6
o
, 20.05
o
, 21.45
o
, 22.1
o
, 25.45
o,
and
28.65
o
leading to its crystalline nature (Fig. 8). These charac-
teristic peaks were not seen and transformed into fused
peaks in the case of the capecitabine-loaded network thereby
proving its amorphous nature. The transformation of capec-
itabine from a crystalline into amorphous nature may be due
to its inclusion into cavities of HP-β-CD. Similar findings
were reported by a study involving HP-β-CD conducted by
Wang and co-workers [24].
3.8. Energy-Dispersive X-ray Spectroscopy (EDX)
Elemental analysis and chemical composition of hydro-
gels were confirmed by energy dispersive spectroscopy, a
surface analysis technique that measures the binding energy
of electrons within atoms of 5-10nm depth. EDX spectra of
capecitabine, unloaded hydrogels and capecitabine-loaded
hydrogels are presented in (Fig. 9). In capecitabine, peaks of
carbon, oxygen, fluorine, and nitrogen were displayed in con-
centrations of 56.06%, 29.54%, 3.87%, and 10.52%, respec-

tively. Peaks of fluorine and nitrogen were absent in unload-
ed hydrogel as these atoms are an integral part of capec-
itabine and these peaks were present in capecitabine loaded
hydrogel thus confirming the successful loading of capec-
itabine into the grafted network. Mahmood and co-workers
confirmed elemental composition and loading of acyclovir
into the developed pH-sensitive network [25]. Confirmation
of capecitabine into the developed carrier system was also
confirmed in a quite similar manner.
3.9. Release Studies
The effects of concentration of HP-β-CD, agarose, and
MBA on the release of capecitabine at pH 1.2 and 7.4 were
investigated (Fig. 10). At pH 1.2, all the formulations (H-
PAG1-HPAG12) were resulted in minimal capecitabine re-
lease i.e. 9.965%-13.651%, while at pH 7.4 it was between
71% to 94.25%. Capecitabine release was significantly im-
proved (p<0.05)with the rise of HP-β-CD, agarose, and
MAA contents, and optimum release was observed in
HPAG3 (94.25%), HPAG6 (90.71%), and HPAG9
(88.11%). Availability of free hydroxy groups (-OH) and car-
boxylic groups (-COOH) from both of the polymers and
MAA, respectively in ionic state at pH 7.4 resulted in repul-
sion between polymeric chains and higher swelling,
promoting the uptake of capecitabine solution, higher load-
ing and higher percentage release of capecitabine. Asghar et
al. have utilized MAA as a pH-sensitive monomer for venla-
faxine release in a controlled fashion. Similar impacts of
MAA were seen in the current study [26].
With the rise of MBA contents, capecitabine release was
decreased up to 82.06% (HPAG12). A higher ratio of cross-
linker contributed to the development of a more dense struc-
ture and poor swelling. So, penetration of physiological
fluid into the network was lowered resulting in the decrease
of capecitabine release [27].
Different kinetic models were applied on capecitabine re-
lease data and based upon the coefficient of regression
(R
2
)values, the best-fit model was zero-order kinetics. Thus,
sustained release of capecitabine from the network was no-
ticed. Exponent “n” value determined the mechanism of
capecitabine release from the carrier system. It was greater
than 0.89 for most of the developed formulations thus high-
lighting Super Case II transport except formulations HPAG3
and HPAG6 which followed non-fickian diffusion (Table 2).
Fig. (8). XRD diffractograms of (A) Capecitabine, (B) agarose, (C)
HP-β-CD and (D) Capecitabine loaded hydrogels. (A higher resolu-
tion / colour version of this figure is available in the electronic
copy of the article).
Fig. (9). EDX spectra of (A) Capecitabine (B) unloaded and (C) capecitabine loaded hydrogels. (A higher resolution / colour version of this

Fig. (10). Capecitabine release from formulations (HPAG1 – HPAG12) at pH1.2 and pH 7.4. (A higher resolution / colour version of this fig-
ure is available in the electronic copy of the article).
Table 2. Results of kinetic modelling on capecitabine release data.
Formulation
Zero-order 1
st
order Higuchi Model Korsmeyer Peppas
R
2
R
2
R
2
R
2
n
HPAG1 0.9925 0.9241 0.8216 0.9961 1.112
HPAG2 0.9871 0.9260 0.8592 0.9875 0.965
HPAG3 0.9694 0.9282 0.8949 0.9812 0.836
HPAG4 0.9906 0.9271 0.8086 0.9972 1.157
HPAG5 0.9877 0.9318 0.8513 0.9877 0.994
HPAG6 0.9678 0.9404 0.8990 0.9819 0.824
HPAG7 0.9882 0.9388 0.8417 0.9885 1.032
HPAG8 0.9882 0.9448 0.8425 0.9885 1.031
HPAG9 0.9830 0.9490 0.8832 0.9878 0.890
HPAG10 0.9865 0.9418 0.8312 0.9879 1.070
HPAG11 0.9816 0.9340 0.8082 0.9879 1.157
HPAG12 0.9856 0.9535 0.8756 0.9883 0.916
3.10. Toxicological Evaluation
To validate the safety of developed hydrogel, different
parameters including body weight, water and food intake,
certain illnesses i.e. fever, diarrhoea, dermal and ocular
toxicity were also monitored for 14 days in the present study
(Table 3). No significant variation in weight, water, and
food intake was noticed in the treated and controlled group
of animals. Ocular and dermal toxicities were absent. Bio-
chemical and haematological analyses of blood samples
were performed on those that have presented acceptable re-
sults (Table 4). Liver, kidney, and lipid profiles were also
within a healthy range (Table 5).

Table 3. Clinical findings during acute oral toxicity studies.
Observations Group I (Control) Group II (Tested)
Signs of illness Not observed Not observed
Bodyweight (Kg)
Pre-treatment 1.98±0.04 2.01±0.04
Day 1 1.98±0.02 2.02±0.03
Day 7 2.03±0.04 2.06±0.04
Day 14 2.06±0.05 2.09±0.04
Water intake (ml)
Pre-treatment 184.16±1.23 189.34±0.12
Day 1 190.45±2.03 193.45±1.71
Day 7 199.17±3.35 200.63±1.25
Day 14 205.13±2.53 204.24±2.25
Food intake(g)
Pretreatment 69.26±1.11 70.31±1.18
Day 1 71.33±1.50 71.20±1.23
Day 7 70.74±1.21 72.39±1.43
Day 14 74.61±1.06 75.471±1.12
Dermal toxicity Not seen Not seen
Ocular toxicity Absent Absent
Mortality Zero Zero
Table 4. Results of biochemical analysis of rabbits’ blood.
Parameters Group I (Control) Group II (Treated with Hydrogels)
Haemoglobin (g/dl) 9.5 11.0
pH 6.99 ± 0.18 7.11 ± 0.30
White blood cells (×10
3
/µl) 2.5 ± 0.41 2.4 ± 0.32
Red blood cells (×10
6
/ µl) 4.72 ± 1.27 4.76 ± 1.41
Platelets (×10
9
L
-1
) 4.46 ± 0.17 4.59 ± 0.17
Monocytes (%) 3.39 ± 0.29 3.48 ± 0.19
Neutrophils (%) 54.47 ± 2.13 54.73 ± 2.16
Lymphocytes (%) 62.65 ± 3.45 62.51 ± 3.24
Mean corpuscular volume (%) 62.5±2.21 63.64 ± 2.33
Mean corpuscular haemoglobin (pg/cell) 20.1±0.71 23.1 ± 0.69
Mean corpuscular haemoglobin conc. (%) 32.2±1.11 32.0 ± 1.09
Table 5. Kidney, liver, and lipid profiles.
Biochemical Analysis Group I (Control) Group II (Treated with Hydrogels)
ALT (IU/L) 159.64 ± 4.21 158.55 ± 5.56
AST (IU/L) 59 ± 3.21 65.57 ± 3.66
Urea (mmol/L) 15.61 ± 0.42 16.62 ± 1.62
Creatinine (mg/dL) 1.91 ± 0.31 1.90 ± 0.11
Uric acid (mg/dL) 4.24 ± 1.14 4.63 ± 1.11
Cholesterol (mg/dL) 62.35 ± 2.42 64.53 ± 2.33
Triglycerides (mg/dL) 60.68 ± 4.45 59.37 ± 4.56

To detect the toxic effects of developed hydrogels on vi-
tal organs histopathological studies were also conducted.
For this purpose rabbits were sacrificed on the 14th
day of
study, vital organs were removed, stored in 10% formalin so-
lution and tissue slides were prepared. Microscopic evalua-
tion of these H & E stained histopathological slides was
made. Both groups (control and tested) did not show any
pathological change in tissues of vital organs (Fig. 11).
Moreover, no signs of degeneration, lesions, inflammation,
and abnormalities were seen. Cardiac tissues of both control
and tested animals revealed a precise pattern of cardiomyo-
cytes without any evidence of hypertrophic cells. There was
no sign of myocardial infarction.
Fig. (11). Histopathological examination of rabbit’s vital organs.
(A higher resolution / colour version of this figure is available in
the electronic copy of the article).
The liver section of control and tested animals displayed
slight hyperplasia in the portal triad region and accumula-
tion of inflammatory cells. An extracellular matrix was also
observed to be deposited around the portal triad. Microscop-
ic evaluation of lung showed emphysema, pulmonary oede-
ma, and hyperplasia. Moreover, alveolar accumulation was
also noted but there was no sign of lung fibrosis. These ab-
normalities were also seen in liver and lung sections of the
control group so these could not be considered as toxic ef-
fects of administered fabricated carrier systems.
The kidneys of rabbits showed no tubular and ductile da-
mage. Normal kidneys were observed having intact glomeru-
lus and bowman capsules in both control and treated groups.
Moreover, a normal spleen was observed having well-differ-
entiated red and white pulp with occasional hemosiderin
crystals. Uniform distribution of white blood cells was noted
in the white pulp. The intestines of rabbits were observed to
be showing normal columnar epithelium. Intact muscularis
was seen with no sign of inflammation or hyperplasia.
Furthermore, photomicrographs of the brain presented
no sign of cellular degeneration and inflammatory cell infil-
tration. Brain cortical regions were intact. Axons were clear
with nuclei and astrocytes were observed to be normal. No
difference was observed among the control group and group
treated with HP-β-CD/agarose-co-poly (MAA) hydrogels.
CONCLUSION
In the current study, capecitabine loaded pH-sensitive
HP-β-CD/agarose-g-poly(MAA) hydrogels were successful-
ly developed, tuned, and characterized for different charac-
teristic features such as drug loading efficiency, structural
and compositional characteristics, thermal stability, swelling
behaviour, morphology, physical form, elemental analysis,
and release kinetics. By optimising the different ingredients,
hydrogel having controlled release characteristics was fabri-
cated. The pH-responsive behaviour of hydrogel was validat-
ed by evaluating the release behaviour of developed hydro-
gel at different pH, showing significantly higher release at
higher pH compared with lower pH. The controlled release
feature of developed hydrogel will be enabled to maintain
the therapeutic levels of capecitabine, improve bioavailabili-
ty and patient compliance. Excellent swelling, high gel con-
tents and high water holding capacity also make these deliv-
ery systems an ideal choice for the delivery of therapeutic
agents having poor bioavailability. For establishing a safety
profile, the developed hydrogels were also tested for acute
oral toxicity in terms of body weight, water and food intake,
dermal toxicity, ocular toxicity, biochemical analysis, and
histological examination of specimens were collected from
treated and tested group animals. The toxicity analysis evi-
denced an excellent safety profile with no signs of oral, der-
mal, or ocular toxicities, as well as no pathologic variations
in blood chemistry and histology. These results evidenced
that the developed hydrogels exhibit excellent pharmaceuti-
cal and therapeutic potential to be employed as smart pH-re-
sponsive hydrogel systems for the controlled delivery of
drugs.

ETHICS APPROVAL AND CONSENT TO PARTICI-
PATE
All the study protocols were reviewed and approved by
the Institutional Research Ethics Committee of Faculty of
Pharmacy, The University of Lahore notification no.
IREC-2019-137A.
HUMAN AND ANIMAL RIGHTS
No humans were used in this study. All animals’ proce-
dures performed were in accordance with the Laboratory An-
imal Care Guidelines.
CONSENT FOR PUBLICATION
Not applicable.
AVAILABILITY OF DATA AND MATERIALS
The authors confirm that the data supporting the findings
of this research are available within the article.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
ACKNOWLEDGMENTS
The authors would like to sincerely acknowledge the
“University of Sargodha and University of Lahore, Lahore,
Pakistan” for providing instrumental support in executing
the present research project.
REFERENCES
Soni, G.; Yadav, K.S. Nanogels as potential nanomedicine carrier
[1]
for treatment of cancer: A mini review of the state of the art. Sau-
di Pharm. J., 2016, 24(2), 133-139.
http://dx.doi.org/10.1016/j.jsps.2014.04.001 PMID: 27013905
Bhattarai, N.; Gunn, J.; Zhang, M. Chitosan-based hydrogels for
[2]
controlled, localized drug delivery. Adv. Drug Deliv. Rev., 2010,
62(1), 83-99.
http://dx.doi.org/10.1016/j.addr.2009.07.019 PMID: 19799949
Mishra, B.; Upadhyay, M.; Reddy, A.S.; Vasant, B.G. Muthu, M.
[3]
Hydrogels: an introduction to a controlled drug delivery device,
synthesis and application in drug delivery and tissue engineering.
Austin J Biomed Eng., 2017, 4, 1037.
Mahmood, A.; Ahmad, M.; Sarfraz, R.M.; Usman, M.U. Develop-
[4]
ment of acyclovir loaded β‐cyclodextrin‐g‐poly methacrylic
acid hydrogel microparticles: an in vitro characterization. Adv. Po-
lym. Technol., 2018, 37, 697-705.
http://dx.doi.org/10.1002/adv.21711
Cal, K.; Centkowska, K. Use of cyclodextrins in topical formula-
[5]
tions: practical aspects. Eur. J. Pharm. Biopharm., 2008, 68(3),
467-478.
http://dx.doi.org/10.1016/j.ejpb.2007.08.002 PMID: 17826046
Maurer, S.; Junghans, A.; Vilgis, T.A. Impact of xanthan gum, su-
[6]
crose and fructose on the viscoelastic properties of agarose hydro-
gels. Food Hydrocoll., 2012, 29, 298-307.
http://dx.doi.org/10.1016/j.foodhyd.2012.03.002
Yuan, Y.; Wang, L.; Mu, R.J.; Gong, J.; Wang, Y.; Li, Y.; Ma, J.;
[7]
Pang, J.; Wu, C. Effects of konjac glucomannan on the structure,
properties, and drug release characteristics of agarose hydrogels.
Carbohydr. Polym., 2018, 190, 196-203.
http://dx.doi.org/10.1016/j.carbpol.2018.02.049 PMID: 29628238
Kelly, C.; Bhuva, N.; Harrison, M.; Buckley, A.; Saunders, M.
[8]
Use of raltitrexed as an alternative to 5-fluorouracil and capec-
itabine in cancer patients with cardiac history. Eur. J. Cancer,
2013, 49(10), 2303-2310.
http://dx.doi.org/10.1016/j.ejca.2013.03.004 PMID: 23583220
Verma, C.; Negi, P.; Pathania, D.; Sethi, V.; Gupta, B. Preparation
[9]
of pH-sensitive hydrogels by graft polymerization of itaconic acid
on tragacanth gum. Polym. Int., 2019, 68, 344-350.
Afinjuomo, F.; Fouladian, P.; Parikh, A.; Barclay, T.G.; Song, Y.;
[10]
Garg, S. Preparation and Characterization of Oxidized Inulin Hy-
drogel for Controlled Drug Delivery. Pharmaceutics, 2019, 11(7),
356.
http://dx.doi.org/10.3390/pharmaceutics11070356 PMID:
31336580
Akalin, G.O.; Pulat, M. Preparation and characterization of κ-car-
[11]
rageenan hydrogel for controlled release of copper and manganese
micronutrients. Polym. Bull., 2020, 77, 1359-1375.
http://dx.doi.org/10.1007/s00289-019-02800-4
Che, Y.; Li, D.; Liu, Y.; Ma, Q.; Tan, Y.; Yue, Q.; Meng, F. Physi-
[12]
cally cross-linked pH-responsive chitosan-based hydrogels with
enhanced mechanical performance for controlled drug delivery.
RSC Advances, 2016, 6, 106035-106045.
http://dx.doi.org/10.1039/C6RA16746B
Kanmaz, N.; Saloglu, D.; Hizal, J. Humic acid embedded chi-
[13]
tosan/poly (vinyl alcohol) pH-sensitive hydrogel: Synthesis, char-
acterization, swelling kinetic and diffusion coefficient. Chem.
Eng. Commun., 2019, 206, 1168-1180.
http://dx.doi.org/10.1080/00986445.2018.1550396
Nesrinne, S.; Djamel, A. Synthesis, characterization and rheologi-
[14]
cal behavior of pH sensitive poly (acrylamide-co-acrylic acid) hy-
drogels. Arab. J. Chem., 2017, 10, 539-547.
http://dx.doi.org/10.1016/j.arabjc.2013.11.027
Farhadnejad, H.; Mortazavi, S.A.; Erfan, M.; Darbasizadeh, B.;
[15]
Motasadizadeh, H.; Fatahi, Y. Facile preparation and characteriza-
tion of pH sensitive Mt/CMC nanocomposite hydrogel beads for
propranolol controlled release. Int. J. Biol. Macromol., 2018, 111,
696-705.
http://dx.doi.org/10.1016/j.ijbiomac.2018.01.061 PMID:
29337099
Zou, C.; Liu, Y.; Yan, X.; Qin, Y.; Wang, M.; Zhou, L. Synthesis
[16]
of bridged β-cyclodextrin–polyethylene glycol and evaluation of
its inhibition performance in oilfield wastewater. Mater. Chem.
Phys., 2014, 147, 521-527.
http://dx.doi.org/10.1016/j.matchemphys.2014.05.025
Nayak, A.K.; Pal, D. Development of pH-sensitive tamarind seed
[17]
polysaccharide-alginate composite beads for controlled diclofenac
sodium delivery using response surface methodology. Int. J. Biol.
Macromol., 2011, 49(4), 784-793.
http://dx.doi.org/10.1016/j.ijbiomac.2011.07.013 PMID:
21816168
Gong, C.Y.; Shi, S.; Dong, P.W.; Yang, B.; Qi, X.R.; Guo, G.;
[18]
Gu, Y.C.; Zhao, X.; Wei, Y.Q.; Qian, Z.Y. Biodegradable in situ
gel-forming controlled drug delivery system based on thermosensi-
tive PCL-PEG-PCL hydrogel: part 1-Synthesis, characterization,
and acute toxicity evaluation. J. Pharm. Sci., 2009, 98(12),
4684-4694.
http://dx.doi.org/10.1002/jps.21780 PMID: 19367619
Qi, X.; Su, T.; Tong, X.; Xiong, W.; Zeng, Q.; Qian, Y.; Zhou, Z.;
[19]
Wu, X.; Li, Z.; Shen, L.; He, X.; Xu, C.; Chen, M.; Li, Y.; Shen,
J. Facile formation of salecan/agarose hydrogels with tunable
structural properties for cell culture. Carbohydr. Polym., 2019,
224, 115208.
http://dx.doi.org/10.1016/j.carbpol.2019.115208 PMID: 31472869
Rasib, S.Z.M.; Muhamad, N.F.; Akil, H.M.; Hamid, Z.A.A.; Te-
[20]
bal, N. Preparation and Characterization of pH-and Tempera-
ture-responsive by Different Composition Chitosan-P (MAA- co-
NIPAM) Hydrogel for Drug Delivery System. Jixie Gongcheng
Xuebao, 2017, 4, 123-133.
Tanan, W.; Panichpakdee, J.; Saengsuwan, S. Novel biodegrad-
[21]
able hydrogel based on natural polymers: Synthesis, characteriza-
tion, swelling/reswelling and biodegradability. Eur. Polym. J.,
2019, 112, 678-687.

http://dx.doi.org/10.1016/j.eurpolymj.2018.10.033
Fekete, T.; Borsa, J.; Takacs, E.; Wojnarovits, L. Synthesis of cel-
[22]
lulose-based superabsorbent hydrogels by high-energy irradiation
in the presence of crosslinking agent. Radiat. Phys. Chem., 2016,
118, 114-119.
http://dx.doi.org/10.1016/j.radphyschem.2015.02.023
Date, P.; Tanwar, A.; Ladage, P.; Kodam, K.M.; Ottoor, D.
[23]
Biodegradable and biocompatible agarose–poly (vinyl alcohol) hy-
drogel for the in vitro investigation of ibuprofen release. Chem.
Pap., 2020, 1, 1-14.
http://dx.doi.org/10.1007/s11696-019-01046-8
Wang, L.L.; Zheng, W.S.; Chen, S.H.; Han, Y.X.; Jiang, J.D. De-
[24]
velopment of rectal delivered thermo-reversible gelling film encap-
sulating a 5-fluorouracil hydroxypropyl-β-cyclodextrin complex.
Carbohydr. Polym., 2016, 137, 9-18.
Mahmood, A.; Ahmad, M.; Sarfraz, R.M.; Minhas, M.U. β-CD
[25]
based hydrogel microparticulate system to improve the solubility
of acyclovir: Optimization through in-vitro, in-vivo and toxicologi-
cal evaluation. J. Drug Deliv. Sci. Technol., 2016, 36, 75-88.
http://dx.doi.org/10.1016/j.jddst.2016.09.005
Asghar, S.; Minhas, M.U.; Ahmad, M.; Khan, K.U.; Sohail, M.;
[26]
Khalid, I. Hydrophobic–hydrophilic cross‐linked matrices for
controlled release formulation of Highly water‐soluble drug ven-
lafaxine: Synthesis and evaluation studies. Adv. Polym. Technol.,
2018, 37, 3146-3158.
http://dx.doi.org/10.1002/adv.22085
Xu, S.; Li, H.; Ding, H.; Fan, Z.; Pi, P.; Cheng, J.; Wen, X. Allylat-
[27]
ed chitosan-poly(N-isopropylacrylamide) hydrogel based on a
functionalized double network for controlled drug release. Carbo-
hydr. Polym., 2019, 214, 8-14.

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